Despite the growing body of evidence to support KSHV as the etiological agent in many AIDS and non-AIDS-related malignancies, understanding how KSHV is involved in these malignancies is important for the generation of therapies against the spectrum of KSHV-associated diseases. This is complicated, however, by the absence of a good animal model. Last year we reported the isolation of a simian virus that is closely related to KSHV that was isolated from a simian immunodeficiency virus (SIV)- infected macaque that developed lymphoproliferative disorders (LPD). This past year, we made the following observations from in vitro and in vivo experiments. 1) By molecular cloning and DNA sequence analysis, we determined that the virus encodes similar cytokine-like genes as KSHV. This indicates that the virus, now referred to as rhesus KSHV (RhKSHV), is more closely related to KSHV than Herpesvirus saimiri. 2) Utilizing polymerase chain reaction (PCR) analysis, we found that viral load was higher in DNA derived from diseased tissue compared to DNA isolated from identical tissue from macaques without disease. Although this does not prove the virus is responsible for the LPD, it supports the notion that the virus may be associated with LPD. 3) Experimental infection of SIVmac239-infected macaques with the RhKSHV resulted in the development of B cell hyperplasia, lymphadenopathy and polyclonal gammopathy, compared to macaques infected with SIVmac239 alone, or macaques co-infected with a strict T lymphocyte-tropic SIV and RhKSHV. These co-infection studies indicate that RhKSHV infection can result in disease manifestations in SIV-infected macaques that have similarities to HIV-infected patients that frequently develop B cell abnormalities.